CN1950330A - Novel crystalline calcium pantothenate - Google Patents
Novel crystalline calcium pantothenate Download PDFInfo
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- CN1950330A CN1950330A CNA2005800138491A CN200580013849A CN1950330A CN 1950330 A CN1950330 A CN 1950330A CN A2005800138491 A CNA2005800138491 A CN A2005800138491A CN 200580013849 A CN200580013849 A CN 200580013849A CN 1950330 A CN1950330 A CN 1950330A
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Abstract
A novel crystalline calcium pantothenate, which is obtainable by a method comprising the following steps: (1) a step of mixing a crystalline calcium pantothenate and an amorphous calcium pantothenate to prepare a uniform mixture, (2) a step of allowing the uniform mixture obtained in the step (1) to absorb moisture, to prepare a crystalline calcium pantothenate, and (3) a step of repeating the steps (1) and (2), using the crystalline calcium pantothenate obtained in the step (2), and which exhibits a ratio (I<16.0>/I<5.1>) of 1 or more, the ratio representing a ratio of the diffraction intensity (I<16.0>) at a diffraction angle (2theta) of 16 DEG to the diffraction intensity (I<5.1>) at a diffraction angle (2theta) of 5.1 DEG . The above crystalline calcium pantothenate is non-hygroscopic and also excellent in fluidity.
Description
Technical field
The present invention relates to novel crystalline calcium pantothenate.
Background technology
Calcium pantothenate (calcium pantothenate: two [(R)-N-(2,4-dihydroxyl-3,3-dimethylbutyl)-β-An Jibingsuan calcium]; Below, abbreviate " PC " in this manual sometimes as) be medicine that Pharmacopeia of Japan recorded, be widely used aspect the treatment of the prevention of pantothenic acid deficiency disease and treatment, contact dermatitis, acute or chronic eczema etc.About the pressed powder of calcium pantothenate, people know the goods of amorphous form, but because the water absorbability of these goods exists and has moisture and the problem of powder agglomates and so on, make, preserve, carrying and must be careful when using.On the other hand, as the pressed powder of crystal type, people know the solventless crystalline of α-type, β-type and γ-type, and crystallization 4CH
3OH1H
2O compound and 1 crystal of hydrate are as recrystallisation solvent compound (about the detail file of these crystallization shapes, with reference to rice wall etc., Chem.Pharm.Bull., 24, pp.3097-3102,1976).As everyone knows, these crystal types PC is non-hygroscopic.
Manufacturing about crystalline calcium pantothenate, people have proposed to utilize organic solvents such as methyl alcohol to concentrate after the PC dissolution of crystals is in water, add methyl alcohol and heating, thereby obtain the method (Levy of non-hygroscopic needle-like crystal (m.p.195 ℃～196 ℃), H.et al., J.Amer.Chem.Soc., 63, pp.2846～2847,1941); Utilize methanol solution to obtain the method (bridge of boats etc., RIKEN's report, 22,681,1943) of the crystallization (m.p.153.5 ℃～154 ℃) different with Levy etc.; In methanol solution, add an amount of water, the method (special public clear 40-2330 communique) that crystallization is separated out; The method (special public clear 49-27168 communique) that the optical activity crystal is separated out; From methanol solution, reclaim the method (spy opens clear 53-108921 communique) of PC; The method for compositions (spy opens flat 3-123729 communique) of preparation and magnesium lactate etc.; When from fermented liquid, reclaiming, in the high density PC of the about 50W/V% degree aqueous solution, add methyl alcohol so that methyl alcohol arrives the method (spy opens flat 9-286 communique) of 90V/V%; And use recombinant chou to make in the PC process, in the high density PC solution of about 45W/W%～55W/W% degree, add the method (spy opens flat 9-135687 communique) of methyl alcohol.In addition, people also know the uniform mixture moisture absorption that comprises crystalline calcium pantothenate and amorphous calcium pantothenate by making, and with an organic solvent do not make the method (international open WO01/98255) of crystalline non-hygroscopic calcium pantothenate in fact.
Yet,, on flowability, exist and compare relatively poor problem with amorphous form though these crystalline calcium pantothenates are non-hygroscopic.In addition, bulk specific gravity (volume of unit weight) is also bigger, is difficult to be fit to operations such as processing, preservation and carrying.At present, do not find to be the non-hygroscopic crystalline calcium pantothenate that has the flowability that is equal to mutually with the goods of amorphous form again as yet.
Summary of the invention
Problem of the present invention is to provide non-hygroscopic crystalline calcium pantothenate, and its flowability is improved.
The present inventor furthers investigate in order to solve above-mentioned problem.Found that, according to the open described method of WO01/98255 in the world, make the uniform mixture moisture absorption that comprises crystalline calcium pantothenate and amorphous calcium pantothenate with after making crystalline calcium pantothenate, in resulting crystallization, add the amorphous calcium pantothenate once more and make uniform mixture, make this mixture moisture absorption to make crystalline calcium pantothenate then, repeat for several times same step by the resulting crystalline calcium pantothenate of further use, can produce the non-hygroscopic crystalline calcium pantothenate that flowability significantly improves.In addition, we also find, pass through powder x-ray diffraction, the diffraction angle of resulting crystalline calcium pantothenate main peak (2 θ) is consistent with known β-type crystalline, but this crystalline calcium pantothenate also has the intensity and known β-type crystallization opposite feature of 2 θ at the peak of 5.1 ° and 16.0 °, is not known novel crystalline calcium pantothenate at present.The present invention is based on that above-mentioned cognition finishes.
That is, by the present invention, provide crystalline calcium pantothenate, it can obtain by the method that comprises the steps:
(1) crystalline calcium pantothenate and amorphous calcium pantothenate are mixed to prepare the step of uniform mixture;
(2) make the uniform mixture moisture absorption that in above-mentioned steps (1), obtains step with the preparation crystalline calcium pantothenate; And
(3) use the crystalline calcium pantothenate that in above-mentioned steps (2), obtains, repeat the step of above-mentioned steps (1) and (2).
The preferred scheme according to the present invention, the ratio that is provided at crystalline calcium pantothenate in the above-mentioned steps (1) is an above-mentioned crystalline calcium pantothenate more than the 30 weight % with respect to the gross weight of uniform mixture; In above-mentioned steps (1), use β-type crystallization as the available above-mentioned crystalline calcium pantothenate of crystalline calcium pantothenate.
From other viewpoint, by the present invention, following crystalline calcium pantothenate is provided, its diffraction angle (2 θ) in powder x-ray diffraction is 1 or more to diffraction angle (2 θ) at the ratio of 16 ° diffracted intensities at 5.1 ° diffracted intensities, preferably from 1 to 3 scope, more preferably from 1.5 to 2.5 scope.This crystalline calcium pantothenate can be by comprising the method manufacturing of above-mentioned step (1)～(3), and diffraction angle (2 θ) has the peak in the position of 5.1 °, 10.3 °, 11.9 °, 16.0 ° and 18.9 °.By the present invention, following crystalline calcium pantothenate also is provided, its 2 θ in powder x-ray diffraction are more than 1 at 5.1 ° diffracted intensity and 2 θ at the ratio of 16 ° diffracted intensity, be preferably from 1 to 3 scope, more preferably from 1.5 to 2.5 scope, and can be by comprising the method manufacturing of above-mentioned step (1)～(3).
Further from other viewpoint, by the present invention, provide the manufacture method of crystalline calcium pantothenate, described method comprises the steps:
(1) crystalline calcium pantothenate and amorphous calcium pantothenate are mixed to prepare the step of uniform mixture;
(2) make the uniform mixture moisture absorption that in above-mentioned steps (1), obtains step with the preparation crystalline calcium pantothenate; And
(3) use the crystalline calcium pantothenate that in above-mentioned steps (2), obtains, repeat the step of above-mentioned steps (1) and (2).
Crystalline calcium pantothenate water absorbability of the present invention is extremely low, although and be crystalline, also have excellent flowability, so had both the flowability of the calcium pantothenate of the non-hygroscopic of present crystalline calcium pantothenate and amorphous form.Therefore, the operability excellence of crystalline calcium pantothenate of the present invention when storage, use also is suitable for plant-scale manufacturing.
Description of drawings
[Fig. 1] shows the figure of β-type crystalline x-ray diffractogram of powder of making in the reference example 1.
β-type crystalline electron micrograph of making in [Fig. 2] reference example 1.
β-type crystalline electron micrograph (enlarged photograph) of making in [Fig. 3] reference example 1.
[Fig. 4] shows the figure of β-type crystalline x-ray diffractogram of powder of making in the reference example 2.
β-type crystalline electron micrograph of making in [Fig. 5] reference example 2.
β-type crystalline electron micrograph (enlarged photograph) of making among [Fig. 6] embodiment 2.
[Fig. 7] is presented at the figure of variation of the x-ray diffractogram of powder of the resultant in the repeating step of embodiment 1.(A) provides the β-type crystalline x-ray diffractogram of powder as crystal seed among the figure; (B) provide the x-ray diffractogram of powder of the 1st multiple resultant; (C) provide the x-ray diffractogram of powder of the 2nd multiple resultant.
[Fig. 8] is presented at the figure of variation of the x-ray diffractogram of powder of the resultant in the repeating step of embodiment 1.Among the figure, (D) provide the x-ray diffractogram of powder of the 3rd multiple resultant; (E) provide the x-ray diffractogram of powder of the 4th multiple resultant; (F) provide the x-ray diffractogram of powder of the 8th multiple resultant;
The electron micrograph of the crystalline calcium pantothenate of making among [Fig. 9] embodiment 1 of the present invention.
The electron micrograph (enlarged photograph) of the crystalline calcium pantothenate of making among [Figure 10] embodiment 1 of the present invention.
The electron micrograph of [Figure 11] amorphous powder.
The electron micrograph (enlarged photograph) of [Figure 12] amorphous powder.
Embodiment
The term that uses among the present invention " crystallinity " is except comprising in fact fully the material of being made up of crystallization, the material that also comprises a spot of pars amorpha, but the material that calcium pantothenate is metamict (can not confirm the state at peak with powder x-ray diffraction in fact) fully do not comprised.Term " crystallinity " should not be interpreted as getting rid of the material that contains pars amorpha on a small quantity." amorphous " is meant the state that can not confirm the peak with powder x-ray diffraction in fact in addition.The term that uses in this specification sheets " non-hygroscopic " is meant, the moisture uptake under 40 ℃, the condition of relative humidity 75% after 24 hours is below 2%, and is preferred below 1%.
Crystalline calcium pantothenate of the present invention is the novel substance that can obtain by the method that comprises the steps:
(1) crystalline calcium pantothenate and amorphous calcium pantothenate are mixed to prepare the step of uniform mixture;
(2) make the uniform mixture moisture absorption that in above-mentioned steps (1), obtains step with the preparation crystalline calcium pantothenate; And
(3) use the crystalline calcium pantothenate that in above-mentioned steps (2), obtains, repeat the step of above-mentioned steps (1) and (2).
In the open WO01/98255 in the world, put down in writing above-mentioned steps (1) and (2), and can implement according to the method that is recorded in this publication particularly.By reference, include the disclosed full content of the open WO01/98255 in the world in this specification sheets disclose.
Above-mentioned steps (1) is for to mix crystalline calcium pantothenate and amorphous calcium pantothenate, thereby manufacturing comprises the step of the uniform mixture of crystalline calcium pantothenate and amorphous calcium pantothenate.The non-hygroscopic crystalline calcium pantothenate of preferred use is made crystalline calcium pantothenate, for example, (" β-type crystallization " is meant as Chem.Pharm.Bull. 24 in this manual can to use non-hygroscopic β-type crystallization, pp.3097-3102,1976 described β-type crystallizations).Except that β-type crystallization, can also use the mixture that comprises α-type crystallization, γ-type crystallization or 1 crystal of hydrate etc., perhaps the crystalline calcium pantothenate except that β-type crystallization.Manufacture method for the amorphous calcium pantothenate of using as raw material has no particular limits, and makes the amorphous calcium pantothenate by the following method but can compatibly use: thus for example the aqueous solution is sprayed, method that warm air drying is made the powder of amorphous; After will filtering by the crystallization of separating out in the methanol solution, thereby with the warm air-dry dry method of making the powder of amorphous.
Preferably make with extra care the high as far as possible calcium pantothenate of degree as the calcium pantothenate that raw material uses.For example, can use the calcium pantothenate made from the methods such as method of having used synthesis method, fermentation method, transgenic technology, and utilize recrystallization or the refining means commonly used to make with extra care, thereby make crystalline calcium pantothenate or amorphous calcium pantothenate.
For crystalline calcium pantothenate and amorphous calcium pantothenate blended method are not particularly limited, but the crystalline calcium pantothenate and the amorphous calcium pantothenate that preferably are prepared into coccoid by mechanically mixing are usually made uniform mixture.Particle diameter for the powder of crystalline calcium pantothenate that uses as raw material or amorphous calcium pantothenate is not particularly limited, for example about 20 μ m～500 μ m.Can utilize in this area method commonly used to carry out the preparation of uniform mixture as the mixing means of solid, preferred powder.
Be not particularly limited for the temperature and humidity of preparation during uniform mixture, for example mixing can be under room temperature and common humidity, for example carries out under 40%RH～80%RH (%RH represents relative humidity, below identical).Also can suitable heat, carry out the preparation of uniform mixture under the state of humidification, operation can also be carried out the 2nd step simultaneously like this.Blending ratio for crystalline calcium pantothenate and amorphous calcium pantothenate is not particularly limited, and the technician can suitably select according to the moisture absorption condition in next procedure, the kind of desirable crystalline calcium pantothenate etc.Usually, with respect to the gross weight of uniform mixture, the ratio of crystalline calcium pantothenate can be set at more than the 10 weight %, about preferred 30 weight %.
Above-mentioned steps (2) is the step that makes the uniform mixture moisture absorption that is included in the crystalline calcium pantothenate that obtains in the above-mentioned steps (1) and amorphous calcium pantothenate.Usually, this moisture absorption step can perhaps stir under optimal temperature and humidity and carry out by above-mentioned uniform mixture is left standstill under optimal temperature and humidity.For temperature and humidity, carry out in sufficient humidity and temperature that the amorphous calcium pantothenate is carried out crystallization with the form of non-hygroscopic crystalline calcium pantothenate.According to the kind of for example uniform mixture, the kind of desirable non-hygroscopic calcium pantothenate etc., by carry out with as the identical test of the described example of the embodiment of international open WO01/98255 8, the technician can easily determine such temperature and humidity.For example, can select suitable combination in the humidity of preferably about 40%RH～about 80%RH from temperature, the about 30%RH～about 90%RH in the scope of room temperature～about 80 ℃.
In the moisture absorption process, the means when stirring are not particularly limited, and can use mechanical stirring device commonly used.In order to carry out the manufacturing of target product efficiently on technical scale, it generally is necessary stirring.In addition, for the term that is used for this specification sheets " stirring ", except stirring operation commonly used, also comprise can reach with the method that stirs identical physical effect (for example, vibration, flow, ultrasonic stirring etc.), must carry out generalized explanation.The non-hygroscopic crystalline calcium pantothenate that obtains in above-mentioned steps (2) is preferably formed by non-hygroscopic crystalline calcium pantothenate in fact, and the crystal material that preferred conduct does not comprise pars amorpha in fact is prepared.In addition, the non-hygroscopic crystallization calcium pantothenate that obtains sometimes comprises and the different types of crystalline calcium pantothenate of crystalline calcium pantothenate that is used for the preparation of uniform mixture, but preferably can obtain β-type crystallization in step (2).The crystalline calcium pantothenate that obtains in above-mentioned steps (2) needn't be implemented drying etc. and handle promptly and can use as the raw material of step (3), but as required, also can use carrying out the raw material of dry back as step (3).Be not particularly limited for drying means, can use the drying machine that can utilize in the art, carry out drying with suitable condition.
Above-mentioned steps (3) is to use as raw material with the crystalline calcium pantothenate that obtains in above-mentioned steps (2), and repeats the step of above-mentioned steps (1) and (2).Can similarly carry out this step with the method for above-mentioned explanation.Be not particularly limited for multiplicity, but at least 1 time, preferred more than 2 times, more preferably more than 5 times, preferred especially more than 8 times.The upper limit for multiplicity is not particularly limited, but surpasses 10 times the effect of improving that repeats to reduce flowability sometimes, therefore considers the industrial production cost, selects the degree below 10 times.
Crystalline calcium pantothenate of the present invention is characterised in that to have characteristic peak in powder x-ray diffraction, though be to be the crystallization that non-hygroscopic has the flowability that is equal to mutually with amorphous form.Crystalline calcium pantothenate of the present invention, diffraction angle in powder x-ray diffraction (2 θ) has the peak in the position of 5.1 °, 10.3 °, 11.9 °, 16.0 ° and 18.9 °, in these peaks, at the diffracted intensity I of 16.0 ° of diffraction angle (2 θ)
16.0To diffracted intensity I 5.1 ° of diffraction angle (2 θ)
5.1Ratio (I
16.0/ I
5.1) be more than 1, be preferably from 1 to 3 scope (in this manual " from " numerical range of expression comprises the numerical value of the lower limit and the upper limit), more preferably from 1.5 to 2.5 scope.
At present, people know " β-type crystallization " (Chem.Pharm.Bull., 24, pp.3097-3102,1976), and this crystallization is at the diffracted intensity I of 16.0 ° of diffraction angle (2 θ)
16.0To diffracted intensity I 5.1 ° of diffraction angle (2 θ)
5.1Ratio (I
16.0/ I
5.1) less than 1, thereby can clearly distinguish with crystalline calcium pantothenate of the present invention.The angle of the value of diffraction angle 2 θ in powder x-ray diffraction is measured when using the K α characteristic X-ray of general copper commonly used, the precision of angle be about ± and 0.1 °.
In addition, obtaining β-type crystalline calcium pantothenate by crystalline growth is needle-like crystal, and relatively therewith, crystalline calcium pantothenate of the present invention is different with above-mentioned β-type crystallization in appearance, is similar to the calcium pantothenate of amorphous form.Because this apparent feature, crystalline calcium pantothenate of the present invention has improved flowability with the β-type crystallization phases of needle-like crystal than significantly, has and the same excellent flowability of the calcium pantothenate of amorphous form.And crystalline calcium pantothenate of the present invention has feature more excellent than the calcium pantothenate of amorphous form on non-hygroscopic, has both the advantage separately of the calcium pantothenate of crystalline calcium pantothenate and amorphous form.
By above-mentioned steps (3), the processing that needn't carry out drying etc. especially just can obtain crystalline calcium pantothenate of the present invention, in above-mentioned steps (3) afterwards, can carry out drying and whole grain etc. to resulting crystalline calcium pantothenate as required and suitably handle.Be not particularly limited for drying means, can use the drying machine that can utilize in the art, carry out drying with suitable condition.
Crystalline calcium pantothenate of the present invention can be used as medicine, and, can suitably be mixed into quasi drug, makeup, processed food, animal-feed, perhaps in order to make these things in the previously prepared composition.In such use form, crystalline calcium pantothenate of the present invention has satisfactory stability, does not also damage the stability of other compositions.In addition, during the preparation aqueous solution, compare, because therefore powder fine dispersion in water of crystalline calcium pantothenate of the present invention has been shortened the time of uniform dissolution, thereby alleviated the operation burden with the calcium pantothenate powder of amorphous.
Embodiment
Below, by embodiment the present invention is further described particularly, but scope of the present invention is not limited to following embodiment.
Use the MultiFlex 2kw of Rigaku Denki Co., Ltd (horizontal type go ニ オ メ one ) as the powder x-ray diffraction device, and in X-ray diffraction is measured, use following condition.
X-ray tube ball target: Cu
Tube voltage: 40kV
Tube current: 20mA
The monochromatization of X ray: monochromator method+PHA (wave height analytical engine The Pattern of Differential)
Slit: 1 ° of divergent slit
1 ° of scatter slit
Receive slit 0.15nm
Sampling interval: 0.02 °
Sweep velocity: 5 °/min
(ASC-6A), speed setting is 60rpm to use changer (サ Application プ Le チ エ Application ジ ヤ) during mensuration.About sample fixer, the 0.8g sample is filled into through sample board, perhaps use the dark type sample board in the end (the about 2mm of the degree of depth).With leaving standstill with the whole sample transfer in the container in mortar, grind with the mortar rod, until there not being big particle fully, sample is filled in each sample fixer according to the described method of process specifications.
About electron microscope observation, behind sample enforcement evaporation, use scanning electronic microscope to observe.The setting multiple is: about 200 times, about 2000 times.
Powder tstr (パ ウ ダ テ ス ) the PT-N type that the mensuration of Powder Physical uses ホ ソ カ ワ ミ Network ロ Application Co., Ltd. to make according to the flow process book, is respectively measured 3 times with extremely general method, adopts its mean value.
Utilize spray-dryer, the calcium pantothenate aqueous solution is carried out drying, thereby obtain the amorphous powder of calcium pantothenate.
The manufacturing of reference example 1: β-type needle-like crystal
According to (Chem.Pharm.Bull., 24, pp.3097-3102,1976) described methods such as rice walls, obtain β-type crystalline calcium pantothenate.At first, the amorphous granulation thing (manufacturing of first Off ア イ Application ケ ミ カ Le Co., Ltd.) of the calcium pantothenate of 5g fully stirred dissolving fully in the 10wt% of 100g aqueous ethanol after, under 25 ℃, leave standstill.The crystallization that filtration under diminished pressure is separated out after 1 day, and carry out reduced pressure at room temperature.After with the powder x-ray diffraction device this crystallization being analyzed, at the diffracted intensity I of 5.1 ° of diffraction angle (2 θ)
5.1Obviously greater than diffracted intensity I 16.0 ° of diffraction angle (2 θ)
16.0, with (Chem.Pharm.Bull., 24, pp.3097-3102,1976) described β-type crystalline x-ray diffractogram of powder unanimities (Fig. 1) such as rice walls.In addition, by this crystalline electron microscope observation (Fig. 2 and 3), the crystallization that confirms gained is length tens of microns a fine needle-like crystal approximately.
A large amount of manufacturings of reference example 2: β-type needle crystal
The calcium pantothenate (amorphous powder) of 40g is joined in the 10wt% aqueous ethanol of 200g, dissolve while at room temperature carry out ultrasonication, so that solution becomes gets evenly.At this moment, a part of sometimes crystallization begins to separate out and some muddy phenomenon can occur.In the time of 40 ℃ of this outstanding muddy water solution of heating, stir.Then, through tens of minutes, crystallization was further separated out, and white casse and viscosity obviously occurred and rose.When have flowability, resulting ingot is pulverized in the crystallization that filtration under diminished pressure is separated out, and carries out the drying under reduced pressure of a few hours under 40 ℃ with vaporizer.On 150 μ m sieves, pulverize dried crystallization gently, carry out whole grain simultaneously.In order to obtain to be used for enough amounts that Powder Physical is measured, obtain the crystallization of 77g altogether for 3 times thereby repeat aforesaid operations.
With powder x-ray diffraction back the discovery analyzed in the crystallization that sees through sieve, the crystallization phases that obtains in this crystallization and the reference example 1 is same, I
5.1Obviously greater than I
16.0, and as (Chem.Pharm.Bull., 24, pp.3097-3102,1976) described diffractogram unanimities (Fig. 4) such as rice walls.In addition, observe in (Fig. 5 and 6), similarly can confirm the fine needle-like crystal of tens of microns of length in the outward appearance of using electron microscope to carry out.
Embodiment 1: the manufacturing of crystalline calcium pantothenate of the present invention
β-type crystallization that 1g is obtained with aqueous ethanol solution and the calcium pantothenate amorphous powder thorough mixing in the 1g reference example 2, under 60 ℃, the environment of 50%RH, resulting mixture is being launched thinly on the porcelain dish and leaving standstill more than 7 hours, thereby to obtain all be the powder that becomes crystalline calcium pantothenate.A little curing takes place in resulting sometimes powder, therefore in this case, uses method on the sieve of 150 μ ms the comminuted solids identical with reference example 2, carries out whole grain by sieve.
With respect to resulting crystalline calcium pantothenate, to carry out thorough mixing with it with the amorphous powder of the calcium pantothenate of measuring again, with above-mentioned operation similarly, under 60 ℃, 50%RH environment, resulting mixture is launched thinly and leaves standstill more than 7 hours on porcelain dish (バ Star ト), thereby to obtain all be the crystallization that becomes crystalline calcium pantothenate.Repeat 8 these operations altogether, obtain the crystalline calcium pantothenate of about 230g.In Fig. 7 and 8, be given in the x-ray diffractogram of powder of the crystalline calcium pantothenate that obtains in the crystalline calcium pantothenate that obtains in the crystalline calcium pantothenate that obtains in initial β-type crystallization of using in this operation, the crystalline calcium pantothenate that in the 1st time operation, obtains, the 2nd operation, the 3rd operation, the crystalline calcium pantothenate that the 4th obtains in operating, the 8th operation.
Can confirm, by repeating to mix the operation with moisture absorption, at the diffracted intensity I of 5.1 ° of diffraction angle (2 θ)
5.1Reduce relatively, at the diffracted intensity I of 16.0 ° of diffraction angle (2 θ)
16.0Increase relatively, the crystalline calcium pantothenate that in the 8th time operation, finally obtains, it is at the diffracted intensity I of 16.0 ° of diffraction angle (2 θ)
16.0To diffracted intensity I 5.1 ° of diffraction angle (2 θ)
5.1Ratio (I
16.0/ I
5.1) be about 1.9 times.In addition, as shown in the electron micrograph (Fig. 9 and 10) of the crystalline calcium pantothenate that obtains in the 8th time the operation, in this crystalline calcium pantothenate, do not contain needle-like crystal substantially, and present and the similar outward appearance of raw material amorphous powder (Figure 11 and 12) with the peculiar corner angle of crystallization more than tens of microns.
Test example 1
Utilize Ka Er-Brigit Fischer (Schmidt) (Karl Fisher) moisture titration apparatus that the moisture amount of the crystalline calcium pantothenate that obtains in the foregoing description 1 is measured, initial stage moisture is 0.96%.After the described crystalline calcium pantothenate of 1g carried out weighing critically, launch in weighing bottle, and left standstill 24 hours in 40 ℃, the constant temperature and humidity machine of 75%RH, observe the weight increasing amount, increasing amount is 0.54%.On the other hand, with same test the water absorbability of the amorphous powder of raw material is measured, this powder initial stage moisture is 2.11%, and the increasing amount of moisture is 5.71%.Amorphous powder after deliquescence causes testing collapses diffusing, does not keep original form.From above result as can be known, crystalline calcium pantothenate of the present invention is a non-hygroscopic.
Test example 2
Powder Physical to the crystalline calcium pantothenate that obtains in the foregoing description 1 is tested.The β that use obtains in reference example 2-the type crystallization in contrast.
[table 1]
| Calcium pantothenate | Pine apparent specific gravity (g/cc) | Real apparent specific gravity (g/cc) | Intensity of compression (%) |
| Embodiment 1 | 0.630 | 0.759 | 16.9 |
| Reference example 2 (β) | 0.170 | 0.376 | 54.8 |
| The amorphous powder | 0.675 | 0.738 | 8.5 |
[table 2]
| Calcium pantothenate | Repose angle (°) | Cave in the angle (°) | Declinate (°) | The metal sheet repose angle (°) |
| Embodiment 1 | 36.0 | 22.6 | 13.4 | 37.3 |
| Reference example 2 (β) | 48.8 | 21.8 | 27.0 | 73.1 |
| The amorphous powder | 33.4 | 20.0 | 13.5 | 35.3 |
Usually, proportion is to be filled into the important parameter of container medium the time as goods, and heavy goods can use small vessels.Intensity of compression is the rerum natura of trying to achieve with (real apparent specific gravity-Song apparent specific gravity)/real apparent specific gravity, and this numerical value provides the volumetric shrinkage that obtains from the difference of the gross density of dredging filling and close filling.This numerical value is big more, and flowability is poor more, thereby blocks spouts such as hopper easily.The certain impact of coniform powder shaping thing when measuring repose angle, the angle on the inclined-plane that the residual stores in back that caves in causes is the angle that caves in, the repose angle and the big more expression flowability in angle of caving in are low more.The difference at the repose angle and the angle that caves in is called declinate, and the big more streamer of declinate (flashing) is high more.Streamer is meant that the powder that comprises a large amount of air etc. has the high workability as liquid suddenly, and the flow of uncontrollable powder and the phenomenon of jet flow occurs.The metal sheet repose angle is meant that with metal scraper (spatula) horizontal positioned, repose angle also can be thought to discharge in the lateral pitch angle when piling up powder thereon, is very big numerical value in the tack powder.
Compare with the amorphous powder, acicular β-type crystalline proportion is obviously little, and is mobile poor.In addition, acicular β-type crystallization tack is strong, causes the possibility height of streamer.This character perhaps makes it circulate as goods when making calcium pantothenate, becomes very big problem when uses such as medical scene.On the other hand, as can be seen, crystalline calcium pantothenate of the present invention has the Powder Physical that is equal to mutually with the amorphous powder, and is making, using isochronous processing excellence.
Industrial applicibility
Crystalline calcium pantothenate hygroscopicity of the present invention is extremely low, although and have crystallinity, still have excellent flowability, have both the flowability of the calcium pantothenate of the non-hygroscopic of present crystalline calcium pantothenate and amorphous form. Therefore, the treatability of crystalline calcium pantothenate of the present invention when storage, use is excellent, is suitable for plant-scale manufacturing.
Claims (7)
1. crystalline calcium pantothenate, this crystalline calcium pantothenate obtains by the method that comprises the steps:
(1) crystalline calcium pantothenate and amorphous calcium pantothenate are mixed to prepare the step of uniform mixture;
(2) make the uniform mixture moisture absorption that in above-mentioned steps (1), obtains step with the preparation crystalline calcium pantothenate; And
(3) use the crystalline calcium pantothenate that in above-mentioned steps (2), obtains, repeat the step of above-mentioned steps (1) and (2).
2. crystalline calcium pantothenate as claimed in claim 1, wherein crystalline calcium pantothenate is more than the 30 weight % with respect to the ratio of the gross weight of uniform mixture in above-mentioned steps (1).
3. crystalline calcium pantothenate as claimed in claim 1, it uses β-type crystallization to obtain as crystalline calcium pantothenate in above-mentioned steps (1).
4. crystalline calcium pantothenate, this calcium pantothenate is in x-ray diffractogram of powder, at the diffracted intensity I of 16 ° of diffraction angle (2 θ)
16.0To diffracted intensity I 5.1 ° of diffraction angle (2 θ)
5.1Ratio (I
16.0/ I
5.1) be more than 1.
5. crystalline calcium pantothenate as claimed in claim 4, wherein above-mentioned ratio is 1.5～2.5.
6. crystalline calcium pantothenate, this calcium pantothenate is made with the described method of claim 1, and in x-ray diffractogram of powder, at the diffracted intensity I of 16 ° of diffraction angle (2 θ)
16.0To diffracted intensity I 5.1 ° of diffraction angle (2 θ)
5.1Ratio (I
16.0/ I
5.1) be more than 1.
7. the manufacture method of crystalline calcium pantothenate, this manufacture method comprises the steps:
(1) crystalline calcium pantothenate and amorphous calcium pantothenate are mixed to prepare the step of uniform mixture;
(2) make the uniform mixture moisture absorption that in above-mentioned steps (1), obtains step with the preparation crystalline calcium pantothenate; And
(3) use the crystalline calcium pantothenate that in above-mentioned steps (2), obtains, repeat the step of above-mentioned steps (1) and (2).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004135092 | 2004-04-30 | ||
| JP135092/2004 | 2004-04-30 |
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| Publication Number | Publication Date |
|---|---|
| CN1950330A true CN1950330A (en) | 2007-04-18 |
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ID=35241602
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800138491A Pending CN1950330A (en) | 2004-04-30 | 2005-04-27 | Novel crystalline calcium pantothenate |
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|---|---|
| JP (1) | JPWO2005105731A1 (en) |
| CN (1) | CN1950330A (en) |
| WO (1) | WO2005105731A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108640852A (en) * | 2018-06-11 | 2018-10-12 | 精晶药业股份有限公司 | A method of adjusting D-VB5 calcium bulk density and granularity |
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|---|---|---|---|---|
| JP2005325080A (en) * | 2004-05-17 | 2005-11-24 | Daiichi Fine Chemical Co Ltd | Composition containing calcium pantothenate and vitamins |
| JP2007238852A (en) * | 2006-03-10 | 2007-09-20 | Toyo Ink Mfg Co Ltd | Method for producing fine organic pigment |
| DE112008001983B4 (en) * | 2007-07-31 | 2023-08-10 | Dsm Ip Assets B.V. | Process for the synthesis of Na-beta-alaninate |
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| US6582940B1 (en) * | 1998-12-25 | 2003-06-24 | Daiichi Fine Chemical Co., Ltd. | Method for producing calcium pantothenate |
| CN1222507C (en) * | 2000-06-23 | 2005-10-12 | 第一精密化学株式会社 | Process for prodn. of calcium pantothenate |
-
2005
- 2005-04-27 CN CNA2005800138491A patent/CN1950330A/en active Pending
- 2005-04-27 JP JP2006512796A patent/JPWO2005105731A1/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108640852A (en) * | 2018-06-11 | 2018-10-12 | 精晶药业股份有限公司 | A method of adjusting D-VB5 calcium bulk density and granularity |
| CN108640852B (en) * | 2018-06-11 | 2020-12-25 | 精晶药业股份有限公司 | Method for adjusting bulk density and granularity of D-calcium pantothenate |
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| WO2005105731A1 (en) | 2005-11-10 |
| JPWO2005105731A1 (en) | 2008-05-15 |
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